Newborn rat response to single vs. combined cGMP-dependent pulmonary vasodilators

Abstract

. Newborn rat response to single versus combined cGMP-dependent pulmonary vasodilators. Am J Physiol Lung Cell Mol Physiol 306: L207-L215, 2014. First published November 15, 2013 doi:10.1152/ajplung.00164.2013.-Inhaled nitric oxide (NO) and other cGMP-or cAMP-dependent pulmonary vasodilators are often used in combination for the treatment of the persistent pulmonary hypertension of the newborn syndrome. There is in vitro evidence to indicate that NO downregulate the pulmonary vascular response to cGMP-dependent agonists raising concern as to whether a synergistic effect is observed when employing a combined strategy in newborns. Hypothesizing that a synergistic effect is absent, we evaluated newborn and juvenile rat pulmonary arteries to determine the individual and combined vasodilatory effect of cGMP-and cAMP-dependent agonists. In precontracted near-resistance pulmonary arteries, the addition of sildenafil reduced vasorelaxation response to NO donor S-nitroso-N-acetyl penicillamine (SNAP). A similar decrease in SNAP-induced vasodilation was observed in arteries pretreated with BAY 41-2272 (10 Ϫ9 M), a soluble guanylate cyclase stimulator cGMP, and its downstream protein kinase activator. cGMP also reduced the vasorelaxant response to the cAMPdependent forskolin. Inhibition of endogenous vascular NO generation enhanced SNAP-induced relaxation. The present data suggest that the mechanism involved in the cGMP desensitization to other relaxant agonists involves downregulation of the small heat shock protein HSP20 and is evident in rat pulmonary and systemic vascular smooth muscle cells. In newborn rats with chronic hypoxia-induced pulmonary hypertension, the combination of sildenafil and inhaled NO resulted in a lesser reduction in pulmonary vascular resistance compared with their individual effect. These data suggest that clinical exposure to one cGMP-dependent pulmonary vasodilator may affect the response to other cGMP-or cAMP-mediated agonists.sildenafil; nitric oxide; pulmonary hypertension; adenosine 3=,5=-cyclic monophosphate; guanosine 3=,5=-cyclic monophosphate THE SUCCESSFUL TRANSITION from fetal to postnatal life depends on a rapid decrease in pulmonary vascular resistance (PVR) at birth. The factors accounting for this dramatic reduction in PVR are incompletely understood, but nitric oxide (NO) is known to play an important role. The maintenance or recurrence of a high PVR postnatally characterizes the persistent pulmonary hypertension of the newborn syndrome (PPHN), a life-threatening condition requiring early and aggressive therapeutic interventions to improve and maintain adequate blood oxygenation (21).Inhaled NO is the standard of care to therapeutically promote pulmonary vasodilation in infants with PPHN, and significant clinical improvement is observed in many infants subjected to this therapy (2, 4). Yet, when response to inhaled NO is absent or partial, the clinical use of alternative agents with pulmonary vasodilatory properties may be contemplated (29).NO is endogenously generated by nitric...

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Recent advances in the mechanisms of lung alveolarization and the pathogenesis of bronchopulmonary dysplasia

“…In a different line, continued work on the inhibition of phosphodiesterase (PDE)5 by Park and coworkers (270) demonstrated that sildenafil modulation of the NO/cGMP pathway promoted alveolarization (assessed by L m ) in the background of hyperoxia. These data highlight PDE5 as a candidate druggable target to drive alveolarization, and this has stimulated additional studies on the interaction between different cGMP-or cAMP-dependent agonists in the pulmonary vasculature in newborn rats (96). Interestingly, working in adult mice, Czövek and coworkers (79) have demonstrated the utility of VIP to stimulate the NO pathway and preserve lung function and structure in the background of hyperoxia in adult rats.…”

Antenatal sildenafil administration to prevent pulmonary hypertension in congenital diaphragmatic hernia (SToP-PH): study protocol for a phase I/IIb placenta transfer and safety study

“…It is primarily marketed for the treatment of erectile dysfunction, but also for treating PHT in adults [ 16 ]. It enhances nitric oxide (NO)-mediated vasodilation [ 17 ], promotes pulmonary angiogenesis and decreases pulmonary arterial remodeling [ 18 , 19 ]. The drug is effective in children above 1 year of age who have PHT [ 20 ].…”